JP6113924B2 - 新規スルホニルアミノベンズアミド化合物 - Google Patents
新規スルホニルアミノベンズアミド化合物 Download PDFInfo
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- JP6113924B2 JP6113924B2 JP2016529446A JP2016529446A JP6113924B2 JP 6113924 B2 JP6113924 B2 JP 6113924B2 JP 2016529446 A JP2016529446 A JP 2016529446A JP 2016529446 A JP2016529446 A JP 2016529446A JP 6113924 B2 JP6113924 B2 JP 6113924B2
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- alkyl
- haloalkyl
- alkoxy
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- CAWFFBLMSQUZPF-UHFFFAOYSA-N 2-(sulfonylamino)benzamide Chemical class NC(=O)C1=CC=CC=C1N=S(=O)=O CAWFFBLMSQUZPF-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 115
- -1 C 1 -C 4 - alkoxy Chemical group 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 241001465754 Metazoa Species 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 244000045947 parasite Species 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 244000079386 endoparasite Species 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 5
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 4
- 125000004749 (C1-C6) haloalkylsulfinyl group Chemical group 0.000 claims description 4
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims description 4
- 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 239000011737 fluorine Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 2
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims 1
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims 1
- 239000002270 dispersing agent Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 241000282465 Canis Species 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 241000244206 Nematoda Species 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 241000607479 Yersinia pestis Species 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 241000243988 Dirofilaria immitis Species 0.000 description 5
- 241000282326 Felis catus Species 0.000 description 5
- 241000935974 Paralichthys dentatus Species 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 229940099686 dirofilaria immitis Drugs 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 241000699694 Gerbillinae Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000013601 eggs Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000004995 haloalkylthio group Chemical group 0.000 description 4
- 244000000013 helminth Species 0.000 description 4
- 238000005342 ion exchange Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000003071 parasitic effect Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 241000242711 Fasciola hepatica Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 244000144972 livestock Species 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- XOGYQVITULCUGU-UHFFFAOYSA-N 3,4,5-trichloroaniline Chemical compound NC1=CC(Cl)=C(Cl)C(Cl)=C1 XOGYQVITULCUGU-UHFFFAOYSA-N 0.000 description 2
- BCLMDQFEQGRRFB-UHFFFAOYSA-N 5-(4-chlorobenzoyl)-2-nitro-N-(3,4,5-trichlorophenyl)benzamide Chemical compound ClC1=CC=C(C(=O)C=2C=CC(=C(C(=O)NC3=CC(=C(C(=C3)Cl)Cl)Cl)C=2)[N+](=O)[O-])C=C1 BCLMDQFEQGRRFB-UHFFFAOYSA-N 0.000 description 2
- JEDLVMNTFAQQRY-UHFFFAOYSA-N 5-(4-chlorobenzoyl)-2-nitrobenzoic acid Chemical compound ClC1=CC=C(C(=O)C=2C=CC(=C(C(=O)O)C=2)[N+](=O)[O-])C=C1 JEDLVMNTFAQQRY-UHFFFAOYSA-N 0.000 description 2
- BMFMOTVRIVPSGS-UHFFFAOYSA-N 5-(4-chlorophenoxy)-2-(methanesulfonamido)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound CS(=O)(=O)NC1=C(C=C(OC2=CC=C(Cl)C=C2)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 BMFMOTVRIVPSGS-UHFFFAOYSA-N 0.000 description 2
- IYVZZSMKXCNKGD-UHFFFAOYSA-N 5-(4-chlorophenoxy)-2-nitro-N-(3,4,5-trichlorophenyl)benzamide Chemical compound [O-][N+](=O)C1=C(C=C(OC2=CC=C(Cl)C=C2)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 IYVZZSMKXCNKGD-UHFFFAOYSA-N 0.000 description 2
- AFSKOMLWCFUJIG-UHFFFAOYSA-N 5-[(4-chlorophenyl)-cyanomethyl]-2-(methanesulfonamido)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound CS(=O)(=O)NC1=C(C=C(C=C1)C(C#N)C1=CC=C(Cl)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 AFSKOMLWCFUJIG-UHFFFAOYSA-N 0.000 description 2
- XCVCVXQXUHWWMN-UHFFFAOYSA-N 5-chloro-2-nitro-N-(3,4,5-trichlorophenyl)benzamide Chemical compound [O-][N+](=O)C1=C(C=C(Cl)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 XCVCVXQXUHWWMN-UHFFFAOYSA-N 0.000 description 2
- 241001147657 Ancylostoma Species 0.000 description 2
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- 241000244186 Ascaris Species 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000253350 Capillaria Species 0.000 description 2
- 241001126268 Cooperia Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 201000006353 Filariasis Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 241000243976 Haemonchus Species 0.000 description 2
- 108010034145 Helminth Proteins Proteins 0.000 description 2
- 241001626440 Joyeuxiella Species 0.000 description 2
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UMAMCCVQWMKGLF-UHFFFAOYSA-N N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-(methanesulfonamido)benzamide Chemical compound FC(C=1C=C(C=C(C=1)C(F)(F)F)NC(C1=C(C=CC(=C1)Br)NS(=O)(=O)C)=O)(F)F UMAMCCVQWMKGLF-UHFFFAOYSA-N 0.000 description 2
- 241001137882 Nematodirus Species 0.000 description 2
- 241000243795 Ostertagia Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000356560 Taenia multiceps Species 0.000 description 2
- 241000244154 Taenia ovis Species 0.000 description 2
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- 241000243774 Trichinella Species 0.000 description 2
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- 150000007513 acids Chemical class 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 230000002141 anti-parasite Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 239000000969 carrier Substances 0.000 description 2
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- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
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- 239000000706 filtrate Substances 0.000 description 2
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000012447 hatching Effects 0.000 description 2
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- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 2
- HJOVHMDZYOCNQW-UHFFFAOYSA-N isophorone Chemical compound CC1=CC(=O)CC(C)(C)C1 HJOVHMDZYOCNQW-UHFFFAOYSA-N 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 230000007653 larval development Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- QPMSONXPAOSXJT-UHFFFAOYSA-N methyl 5-[(4-chlorophenyl)-cyanomethyl]-2-nitrobenzoate Chemical compound ClC1=CC=C(C=C1)C(C=1C=CC(=C(C(=O)OC)C=1)[N+](=O)[O-])C#N QPMSONXPAOSXJT-UHFFFAOYSA-N 0.000 description 2
- QDPZOIXFPCHMLR-UHFFFAOYSA-N methyl 5-bromo-2-(methanesulfonamido)benzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1NS(C)(=O)=O QDPZOIXFPCHMLR-UHFFFAOYSA-N 0.000 description 2
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FUWVMBCPMRAWPG-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-hydroxyoctadecanoate Chemical compound CCCCCCCCCCCCCCCCC(O)C(=O)OCC(O)CO FUWVMBCPMRAWPG-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- JWHNSYSSQVUJIJ-UHFFFAOYSA-N 2-amino-5-(4-chlorobenzoyl)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound NC1=C(C(=O)NC2=CC(=C(C(=C2)Cl)Cl)Cl)C=C(C=C1)C(C1=CC=C(C=C1)Cl)=O JWHNSYSSQVUJIJ-UHFFFAOYSA-N 0.000 description 1
- MLZOTIHLJQSLIN-UHFFFAOYSA-N 2-amino-5-(4-chlorophenoxy)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound NC1=C(C=C(OC2=CC=C(Cl)C=C2)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 MLZOTIHLJQSLIN-UHFFFAOYSA-N 0.000 description 1
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- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
- A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
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- A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
- A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
- A01N41/04—Sulfonic acids; Derivatives thereof
- A01N41/06—Sulfonic acid amides
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
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- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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Description
(式中、
Xは、O、S、NR2C(O)、C(CN)またはCH=CHであり;
R0は、H、C1〜C4−アルキルまたはヒドロキシルであり;
nは、0または1であり;
各Rは、独立して、ハロゲン;C1〜C6−アルキル;C1〜C6−ハロアルキル;C3〜C6−シクロアルキル;C3〜C6−ハロシクロアルキル;アミノ;N−モノ−C1〜C4−アルキルアミノまたはN,N−ジ−C1〜C4−アルキルアミノ;ヒドロキシ;C1〜C6−アルコキシ;C1〜C6−ハロアルコキシ;C1〜C6−アルキルチオ;C1〜C6−ハロアルキルチオ;C1〜C6−アルキル−スルフィニル;C1〜C6−ハロアルキルスルフィニル;C1〜C6−アルキルスルホニル;C1〜C6−ハロアルキルスルホニル;SF5;トリ−C1〜C4−アルキルシリル;C1〜C6−アルコキシカルボニル;アミノカルボニル;N−モノ−C1〜C6−アルキルアミノカルボニルまたはN,N−ジ−C1〜C6−アルキルアミノカルボニル;アミノスルホニル;N−モノ−C1〜C6−アルキルアミノスルホニルまたはN,N−ジ−C1〜C6−アルキルアミノスルホニル;N−C1〜C6−アルキルスルホニルアミノ;C1〜C6アルコキシカルボニルアミノ;N−C1〜C4−アルキル−N−C1〜C6−アルコキシカルボニルアミノ;シアノ;ニトロ;あるいは非置換であるかまたはハロゲン、C1〜C4−アルキル、C1〜C4−ハロアルキル、C3〜C6−シクロアルキル、C1〜C4−アルコキシ、C1〜C4−ハロアルコキシ、アミノ、シアノもしくはニトロによって置換されているC3〜C6−ヘテロシクリルであり;
mは、0〜4の整数であり;
各R1は、独立して、ハロゲン;C1〜C6−アルキル;C1〜C6−ハロアルキル;C3〜C6−シクロアルキル;C3〜C6−ハロシクロアルキル;C1〜C6−アルコキシ;C1〜C6−ハロアルコキシ;C1〜C6−アルキルチオ;C1〜C6−ハロアルキルチオ;C1〜C6−アルキル−スルフィニル;C1〜C6−ハロアルキルスルフィニル;C1〜C6−アルキルスルホニル;C1〜C6−ハロアルキルスルホニル;SF5;アミノ;N−モノ−C1〜C6−アルキルアミノまたはN,N−ジ−C1〜C6−アルキルアミノ;トリ−C1〜C4−アルキルシリル;C1〜C6−アルコキシカルボニル;アミノカルボニル;N−モノ−C1〜C6−アルキルアミノカルボニルまたはN,N−ジ−C1〜C6−アルキルアミノカルボニル;N,N−ジ−C1〜C4−アルキルアミノ−C1〜C4−アルキルアミノカルボニル;アミノスルホニル;N−モノ−C1〜C6−アルキルアミノスルホニルまたはN,N−ジ−C1〜C6−アルキルアミノスルホニル;N−C1〜C6−アルキルスルホニルアミノ;C1〜C6−アルコキシカルボニルアミノ;N−C1〜C4−アルキル−N−C1〜C6−アルコキシカルボニルアミノ;シアノ;ニトロ;ヒドロキシ;B(OH)2;あるいはそれぞれ、非置換であるかまたはハロゲン、C1〜C4−アルキル、C1〜C4−ハロアルキル、C3〜C6−シクロアルキル、C1〜C4−アルコキシ、C1〜C4−ハロアルコキシ、アミノ、シアノもしくはニトロによって置換されているフェニル、ベンゾイル、C3〜C6−ヘテロシクリル、C3〜C6−ヘテロシクリルオキシまたはC6〜C8−ベンゾヘテロシクリルであり;
rは、1〜4の整数である)。
(式中、R、R0、R1、mおよびrは、それぞれ、上記の所定の意味を有し、優先順位も同様である)。好ましい実施形態は、式(Ia)の化合物(式中、R0はHであり、mは1、2または3(とりわけ1または2)であり、rは2または3(とりわけ2)であり、RおよびR1について、それぞれ上記の所定の意味および優先順位を適用する)に関する。特定の好ましい実施形態は、式(Ia)の化合物(式中、R0はHであり、mは1または2であり、rは2または3であり、各Rは、独立して、ハロゲン、C1〜C2−アルキル、C1〜C4−ハロアルキル、C1〜C4−アルコキシ、C1〜C4−ハロアルコキシ、C1〜C4−アルキルスルホニル、トリメチルシリル、N,N−ジ−C1〜C2−アルキルアミノスルホニル、N−C1〜C2−アルキル−N−C1〜C4−アルコキシカルボニルアミノ、シアノ、ニトロまたはピロリジニルであり、各R1は独立してC1〜C4−ハロアルキルである)に関する。とりわけ好ましい実施形態は、式(Ia)の化合物(式中、R0はHであり、mは1または2であり、rは2であり、各Rは独立してハロゲンまたはCF3であり、R1はCF3である)に関する。
(式中、Rおよびmについて、それぞれ上記の所定の意味および優先順位を適用する)。
(式中、R、R1、mおよびrについて、それぞれ上記の所定の意味および優先順位を適用する)。好ましい実施形態は、式(Ib)の化合物(式中、mは1または2(とりわけ1)であり、rは2または3であり、RおよびR1について、それぞれ上記の所定の意味および優先順位を適用する)に関する。特定の好ましい実施形態は、式(Ia)の化合物(式中、mは1であり、rは2または3であり、各Rは、ハロゲン、C1〜C3−ハロアルキル、C1〜C2−アルコキシまたはシアノであり、各R1は、独立して、ハロゲン、C1〜C2−アルキル、C1〜C3−ハロアルキル、C1〜C2−アルコキシ、C1〜C3−ハロアルコキシ、C1〜C2−ハロアルキルチオ、SF5、ニトロまたはヒドロキシである)に関する。とりわけ好ましい実施形態は、式(Ib)の化合物(式中、mは1であり、rは2または3であり、RはハロゲンまたはCF3(特に塩素)であり、各R1はハロゲンまたはCF3である)に関する。
(式中、記号aおよびbはそれぞれ独立して0または1であり、(Hal)はハロゲンであり、RはハロゲンまたはCF3(特にハロゲン)である)に関する。上記の式(Ib’)において、記号aおよびbのうちの1つは好ましくは1であり、他のものは0または1である。
(式中、R0、R1およびrはそれぞれ、上で定義された通りであり、LGは離脱基(例えば臭素等のハロゲン)である)を、式(III)の化合物
(式中、Rおよびmはそれぞれ上で定義された通りである)と、パラジウム触媒の存在下において、反応させることによって調製することができる。鈴木反応と呼ばれるこのパラジウムに触媒された炭素−炭素結合形成反応の詳細は、有機化学の教科書に記載される。
を、式(V)の化合物
(式中、LG’は離脱基(例えばハロゲン、C1〜C2アルコキシまたはヒドロキシル)であり、更なる記号はそれぞれ、上に記載した意味を有する)と、反応させることによる公知のプロセスに従って調製することができる。アミンとカルボン酸またはその誘導体からのアミド形成は、有機化学の教科書に記載される。例えば、式(IV)の化合物は公知であるか、または公知の様式でメタンスルホニルクロリドと対応するアミンを反応させることによる公知のプロセスに従って調製することができる。式(III)および(V)の化合物は商業的に入手可能な公知の化合物である。
を、式(VII)の化合物
(式中、記号は上で定義された通りである)と反応させ、続いてニトロ基を還元し、もたらされたアミンをメタンスルホニルクロリドと更に反応させることによって調製することができる。式(VI)の化合物は式(II)の化合物に類似して調製することができる。
を、式(V)の化合物
(式中、各記号は上に記載した意味を有する)と反応させ、続いてニトロ基を還元し、もたらされたアミンをメタンスルホニルクロリドと更に反応させることによっても調製することができる。代替のものにおいて、式(VIII)の化合物のニトロ基をまず還元し、もたらされたアミノ基をメタンスルホニルクロリドと反応させ、その後式(V)の化合物との反応を遂行することができる。
を、式(X)の化合物
と反応させ、式(VIIIa)の化合物
をもたらすことによって、それ自体は公知である様式で調製することができ、式(VIIIa)の化合物は、例えば水溶性媒質中の強塩基(水酸化リチウム等)による作用によって、式(VIIIb)の化合物
へ更に転換することができる。
10mLの1ピリジン中のメチル2−アミノ−5−ブロモベンゾアート(2.8g)のN2により脱気された溶液を、0℃へ冷却し、その後メタンスルホニルクロリド(0.9mL)を滴加した。反応混合物を室温で一晩撹拌し、次いで50mLの酢酸エチルにより希釈した。有機層をNa2CO3の飽和溶液、ブラインにより洗浄し、次いでMgSO4の上で乾燥し、蒸発乾固した(収率:82%)。
LCMS(方法B):1.55分で305.6(M−H)−。
メチル5−ブロモ−2−(メチルスルホンアミド)ベンゾアート(3.15g)をTHF(20mL、1/1)中で懸濁した。4NのNaOH(6.9mL)を添加し、反応混合物を還流下で4時間撹拌した。完了に際して、反応混合物を2NのHCl(1mL)により処理し、酢酸エチルにより2回抽出した。合わせた有機層をH2O、ブラインにより洗浄し、Na2SO4の上で乾燥し、濾過し、蒸発乾固した。表題生成物はLCMSによって十分に純粋であり、更なる精製なしで次の工程で使用できる(収率:66%)。
LCMS(方法B):1.2分で291.64(M−H)−。
5−ブロモ−2−(メチルスルホンアミド)安息香酸(2.4g)を、還流下で塩化チオニル(23mL)により4時間処理した。過剰のSOCl2を真空下で除去した。CH2Cl2(20mL)を塩化アシルへ添加した。0℃で、10mLのCH2Cl2中の3,5−ビス(トリフルオロメチル)アニリン(1.4mL)およびNEt3(5.68mL)を、緩慢に添加した。反応混合物を放置して暖め、室温で一晩撹拌した。反応混合物を30mLのCH2Cl2により希釈した。20mLのHCl(2N)および20mLのH2Oを添加し、黄色沈殿物が形成されるまで混合物を撹拌した。沈殿物を濾過により除き、高真空下で乾燥し、その後分析した(収率:67%)。
LCMS(方法B):1.99分で502.93(M−H)−。
N2下のジオキサン/H2O(4mL、1/1)中のN−(3,5−ビス(トリフルオロメチル)フェニル)−5−ブロモ−2−(メチルスルホンアミド)ベンズアミド(0.5g)および2−クロロ−4(トリフルオロメチル)ベンゼンボロン酸(286mg)の溶液へ、Na2CO3(636mg)および(1,1’−ビス−ジフェニルホスフィノ−フェロセン)パラジウム−II−ジクロライド(Pd(dppf)Cl2.CH2Cl2、366mg)を添加した。反応混合物を85℃で1時間撹拌した。それを酢酸エチルにより希釈し、セライトを介して濾過した。濾液をH2O、ブラインにより洗浄し、Na2SO4の上で乾燥し、濾過し、蒸発乾固した。粗製混合物を、100%ヘプタンから60%ヘプタン/40%酢酸エチルへの勾配により溶出するフラッシュクロマトグラフィーによって精製して、37%の収率で表題化合物を得た。
LCMS(方法C):2.32分で604.7(M+H)+。
(式中、(R)mの意味は表1中で与えられる)である。
工程A:5−クロロ−2−ニトロ−N−(3,4,5−トリクロロフェニル)ベンズアミド。
5−クロロ−2−ニトロ安息香酸(10g)を還流下で塩化チオニル(7.2mL)により4時間処理した。過剰のSOCl2を真空下で除去した。CH2Cl2(100mL)を塩化アシルへ添加した。0℃で、100mLのCH2Cl2中の3,4,5−トリクロロアニリン(9.7g)およびNEt3(13.8mL)を、緩慢に添加した。反応混合物を放置して暖め、室温(RT)で一晩撹拌した。
LCMS(方法B):1.97分で380.59(M+H)+。
DMA中の5−クロロ−2−ニトロ−N−(3,4,5−トリクロロフェニル)ベンズアミド(8.77g)、K2CO3(6.7g)および4−クロロフェノール(3.26g)を、140℃で14時間加熱した。反応混合物をH2O(100mL)中に注ぎ、沈殿物を濾過により除き、高真空下で乾燥して、茶色固体を得た(収率:55%)。
LCMS(方法B):2.25分で468.45(M−H)−。
N2下で、80mLのEtOH/H2O(3/1)中の5−(4−クロロフェノキシ)−2−ニトロ−N−(3,4,5−トリクロロフェニル)ベンズアミド(13.2g)を、Fe(10.9g)および25%のHCl(0.6mL)により処理し、反応混合物を室温で4時間撹拌した。還元が完了した時に、反応混合物をセライトのプラグ上で濾過し、酢酸エチルにより洗浄した。濾液を真空下で蒸発させた。酢酸エチルを添加し、有機層をブラインにより洗浄し、MgSO4の上で乾燥し、蒸発乾固した(収率:89%)。
LCMS(方法B):2.41分で442.54(M+H)+。
50mLのCH2Cl2中の2−アミノ−5−(4−クロロフェノキシ)−N−(3,4,5−トリクロロフェニル)ベンズアミド(9g)のN2により脱気された溶液へ、ピリジン(8.2mL)を添加した。混合物を0℃へ冷却し、その後メタンスルホニルクロリド(1.6mL)を滴加した。反応混合物を室温で一晩撹拌し、次いで追加の50mLのCH2Cl2により希釈した。有機層をNa2CO3の飽和溶液、ブラインにより洗浄し、次いでMgSO4の上で乾燥し、蒸発乾固した(収率:81%)。
LCMS(方法B):2.27分で518.5(M+H)+。
工程A:メチル5−((4−クロロフェニル)(シアノ)メチル)−2−ニトロベンゾアート。
NaH(140mg)を10mLのDMF中で懸濁した。2mLのDMF中の2−(4−クロロフェニル)アセトニトリル(600mg)を、反応混合物へ0℃で滴加し、次いで室温で2時間撹拌した。混合物を0℃へ冷却し、その後1.5mLのDMF中で溶解したメチル5−クロロ−2−ニトロベンゾアート(1.024g)を滴加した。反応物を0℃で2時間、次いで室温で一晩撹拌した。ジイソプロピルエーテルを添加し、混合物をH2O、ブラインにより洗浄し、Na2SO4の上で乾燥し、濾過し、蒸発乾固した。粗製生成物を準分取HPLC上で精製して、12%の収率で表題化合物を得た。
LCMS(方法B):1.75分で328.84(M−H)−。
メチル5−((4−クロロフェニル)(シアノ)メチル)−2−ニトロベンゾアートを実施例2の工程Cと類似する様式で還元した(収率:96%)。
LCMS(方法B):1.72分で300.88(M+H)+。
メチル2−アミノ−5−((4−クロロフェニル)(シアノ)メチル)ベンゾアートは実施例2の工程Dと類似する様式でスルホニル化した(収率:55%)。
LCMS(方法B):1.71分で376.76(M−H)−。
メチル5−((4−クロロフェニル)(シアノ)メチル)−2−(メチルスルホンアミド)ベンゾアート(50mg)をMeOH/H2O(1mL、1/1)中で懸濁した。NaOH(6mg)を添加し、反応混合物を室温で一晩撹拌した。完了に際して、反応混合物を2NのHCl(1mL)により処理し、酢酸エチルにより2回抽出した。合わせた有機層をH2O、ブラインにより洗浄し、Na2SO4の上で乾燥し、濾過し、蒸発乾固した。表題生成物はLCMSによって十分に純粋であり、更なる精製なしで次の工程で使用できる。
LCMS(方法B):1.52分で362.71(M−H)−。
5−((4−クロロフェニル)(シアノ)メチル)−2−(メチルスルホンアミド)安息香酸(48mg)を、CH2Cl2(1.5mL)中で溶解した。3,4,5トリクロロアニリン(31mg)、ベンゾトリアゾール−1−イル−オキシトリ−ピロリジノホスホニウムヘキサフルオロホスファート(Pybop、75mg)およびジイソプロピルエチルアミン(DIPEA、69□L)を添加した。反応混合物を室温で一晩撹拌した。H2Oを添加し、混合物をCH2Cl2により抽出した。合わせた有機層をNa2CO3の飽和溶液、ブラインにより洗浄し、濾過し、蒸発乾固した。粗製生成物を準分取HPLC上で精製して、46%の収率で表題化合物を得た。
LCMS(方法B):2.15分で539.58(M−H)−。
工程A:5−(4−クロロベンゾイル)−2−ニトロ安息香酸。
メチル5−((4−クロロフェニル)(シアノ)メチル)−2−ニトロベンゾアート(150mg、工程A実施例3を参照)を、THF/H2O(4/1、5mL)中のLiOH(6当量)により室温で一晩処理した。追加の6当量のLiOHを添加した。反応は72時間後に完了した。pH1〜2を達成するまで2NのHClを添加し、次いで反応混合物を酢酸エチルにより2回抽出した。合わせた有機層をH2O、ブラインにより洗浄し、Na2SO4の上で乾燥し、濾過し、蒸発乾固した。表題化合物は工程Bにおける使用のために十分に純粋であった。
LCMS(方法B):1.54分で303.85(M−H)−。
5−(4−クロロベンゾイル)−2−ニトロ安息香酸を、実施例3、工程Eで記述されるものと類似する様式で処理した(収率:71%)。
LCMS(方法B):2.20分で480.57(M−H)−。
5−(4−クロロベンゾイル)−2−ニトロ−N−(3,4,5−トリクロロフェニル)ベンズアミドを、実施例3、工程B中で記述されるものと類似する様式で処理した(収率:93%)。
LCMS(方法B):2.31分で450.61(M−H)−。
2−アミノ−5−(4−クロロベンゾイル)−N−(3,4,5−トリクロロフェニル)ベンズアミドを、実施例2、工程D中で記述されるものと類似する様式で処理した(収率:18%)。
LCMS(方法B):2.23分で530.5(M+H)+。
(式中、(R1)r、(R)mおよびXの意味は表2中で与えられる)である。以下の物理的データは、上述のHPLC/MSによる特徴づけプロセスに従って得られる。
(式中、Yの意味は表3中で与えられる)である。以下の物理的データは、上述のHPLC/MSによる特徴づけプロセスに従って得られる。
生物学的実施例:
採取し浄化した新鮮な線虫卵を、抗寄生虫活性について評価する試験物質および培地を含有する適切にフォーマットされたウェルプレートへの播種に使用し、卵から3齢幼虫へ完全に発生させた。プレートを25℃および60%相対湿度で6日間インキュベーションする。卵の孵化およびその後に続く幼虫の発生を記録して、可能な線虫駆除活性を確認する。有効性は、卵の孵化の減少、3齢幼虫の発生の減少、または任意のステージでの幼虫の麻痺および死のパーセントで表現される。化合物番号1.9〜1.13、1.21〜1.23、1.25、1.26、2.13、2.50、2.51および2.54は、10ppmで≧60%有効性を達成し、したがって活性があると判断される。
採取し浄化した新鮮なDirofilaria immitisのミクロフィラリアを、ドナー動物のイヌの血液から調製する。次いで、ミクロフィラリアを、抗寄生虫活性について評価する試験物質を含有するフォーマットされたマイクロプレート中に分散させる。プレートを25℃および60%相対湿度(RH)で48時間インキュベーションする。次いでミクロフィラリアの運動性を記録して、有効性を決定する。有効性は、対照および標準と比較した運動性の減少のパーセントで表現される。化合物番号1.1〜1.25、2.1〜2.58および3.1〜3.10は、10ppmで50%より上の有効性を示し、したがって活性があると判断される。
アレチネズミを、80匹のA.viteaeの3齢幼虫の皮下注射によって人工的に感染させる。製剤化された試験化合物の強制投与による処理を、感染5日〜9日後に連続的に行う。感染84日後に、アレチネズミから採血し、Fuchs−Rosenthal血球計算板および顕微鏡を使用して血中循環するミクロフィラリアをカウントする。プラセボ処理群よりも少なくとも50%低い血中循環するミクロフィラリアの平均の試験群のみを、完全に解剖して、成虫を回収する。有効性は、Abbotの式を使用して、プラセボ処理群と比較した虫数の%減少として表現される。化合物番号1.5、1.10、1.13、1.17、2.1、2.21、2.26および2.51は、10mg/kgで80%より上の有効性を示した。
ウシまたはヒツジの肝臓から採取した新鮮な成体Fasciola hepaticaを、4mLのRPMI完全培地と共に12ウェルプレート(1ウェルあたりの1匹の吸虫)中に分配し、およそ37℃で12時間インキュベーター中で維持した。培地の更新後に、吸虫の生存率を個々の吸虫の移動のビデオの記録によって決定する(初期値)。試験化合物を100μg/mLの濃度で添加し、吸虫の移動を6時間および24時間後に測定する。有効性は、初期値および無処理対照に基づいて、移動の減少のパーセントとして表現される。この試験において、6時間後に>90%および24時間後に>95%の有効性を示した以下の実施例(1.5、1.10、1.13、2.19、2.21、2.26および2.48)は、陽性と判断される。
Claims (16)
- 式(I)の化合物またはその塩もしくは鏡像異性体:
(式中、
Xは、O、S、NH、C(O)、C(CN)またはCH=CHであり;
R0は、H、C1−C4−アルキルまたはヒドロキシルであり;
nは、0または1であり;
各Rは、独立して、ハロゲン;C1〜C6−アルキル;C1〜C6−ハロアルキル;C3〜C6−シクロアルキル;C3〜C6−ハロシクロアルキル;アミノ;N−モノ−C1〜C4−アルキルアミノまたはN,N−ジ−C1〜C4−アルキルアミノ;ヒドロキシ;
C1〜C6−アルコキシ;C1〜C6−ハロアルコキシ;C1〜C6−アルキルチオ;C1〜C6−ハロアルキルチオ;C1〜C6−アルキル−スルフィニル;C1〜C6−ハロアルキルスルフィニル;C1〜C6−アルキルスルホニル;C1〜C6−ハロアルキルスルホニル;SF5;トリ−C1〜C4−アルキルシリル;C1〜C6−アルコキシカルボニル;アミノカルボニル;N−モノ−C1〜C6−アルキルアミノカルボニルまたはN,N−ジ−C1〜C6−アルキルアミノカルボニル;アミノスルホニル;N−モノ−C1〜C6−アルキルアミノスルホニルまたはN,N−ジ−C1〜C6−アルキルアミノスルホニル;N−C1〜C6−アルキルスルホニルアミノ;C1〜C6−アルコキシカルボニルアミノ;N−C1〜C4−アルキル−N−C1〜C6−アルコキシカルボニルアミノ;シアノ;ニトロ;あるいは非置換であるかまたはハロゲン、C1〜C4−アルキル、C1〜C4−ハロアルキル、C3〜C6−シクロアルキル、C1〜C4−アルコキシ、C1〜C4−ハロアルコキシ、アミノ、シアノもしくはニトロによって置換されているC3〜C6−ヘテロシクリルであり;
mは、0〜4の整数であり;
各R1は、独立して、ハロゲン;C1〜C6−アルキル;C1〜C6−ハロアルキル;C3〜C6−シクロアルキル;C3〜C6−ハロシクロアルキル;C1〜C6−アルコキシ;C1〜C6−ハロアルコキシ;C1〜C6−アルキルチオ;C1〜C6−ハロアルキルチオ;C1〜C6−アルキル−スルフィニル;C1〜C6−ハロアルキルスルフィニル;C1〜C6−アルキルスルホニル;C1〜C6−ハロアルキルスルホニル;SF5;アミノ;N−モノ−C1−C6−アルキルアミノまたはN,N−ジ−C1〜C6−アルキルアミノ;トリ−C1〜C4−アルキルシリル;C1〜C6−アルコキシカルボニル;アミノカルボニル;N−モノ−C1〜C6−アルキルアミノカルボニルまたはN,N−ジ−C1〜C6−アルキルアミノカルボニル;N,N−ジ−C1〜C4−アルキルアミノ−C1〜C4−アルキルアミノカルボニル;アミノスルホニル;N−モノ−C1〜C6−アルキルアミノスルホニルまたはN,N−ジ−C1〜C6−アルキルアミノスルホニル;N−C1〜C6−アルキルスルホニルアミノ;C1〜C6−アルコキシカルボニルアミノ;N−C1〜C4−アルキル−N−C1〜C6−アルコキシカルボニルアミノ;シアノ;ニトロ;ヒドロキシ;B(OH)2;あるいはそれぞれ、非置換であるかまたはハロゲン、C1〜C4−アルキル、C1〜C4−ハロアルキル、C3〜C6−シクロアルキル、C1〜C4−アルコキシ、C1〜C4−ハロアルコキシ、アミノ、シアノもしくはニトロによって置換されている、フェニル、ベンゾイル、C3〜C6−ヘテロシクリル、C3〜C6−ヘテロシクリルオキシまたはC6〜C8−ベンゾヘテロシクリルであり;
rは、1〜4の整数である)。 - 各Rが、独立して、ハロゲン;C1〜C4−アルキル;C1〜C4−ハロアルキル;アミノ;C1〜C4−アルコキシ;C1〜C4−ハロアルコキシ;C1〜C4−ハロアルキルチオ;C1〜C4−アルキルスルホニル;C1〜C4−ハロアルキルスルホニル;トリ−C1〜C2−アルキルシリル;C1〜C4−アルコキシカルボニル;N−モノ−C1〜C4−アルキルアミノカルボニルまたはN,N−ジ−C1〜C4−アルキルアミノカルボニル;アミノスルホニル;N−モノ−C1〜C4−アルキルアミノスルホニルまたはN,N−ジ−C1〜C4−アルキルアミノスルホニル;N−C1〜C2−アルキル−N−C1〜C4−アルコキシカルボニルアミノ;シアノ;ニトロ;あるいは非置換であるかまたはハロゲン、C1〜C2−アルキル、C1〜C2−ハロアルキルもしくはC1〜C2−アルコキシによって置換されている、O、SおよびNから選択される1つまたは2つの同じもしくは異なるヘテロ原子を含む5員または6員のヘテロシクロアルキルである、請求項1に記載の式(I)の化合物。
- 各Rが、ハロゲン、C1〜C2−アルキル、C1〜C2−ハロアルキル、C1〜C2−アルコキシ、C1〜C2−ハロアルコキシまたはシアノである、請求項1に記載の式(I)の化合物。
- 各Rが、塩素、フッ素またはCF 3 である、請求項3に記載の式(I)の化合物。
- mが1、2または3の整数である、請求項1〜4のいずれか一項に記載の式(I)の化合物。
- 各R1が、独立して、ハロゲン;C1〜C4−アルキル;C1〜C4−ハロアルキル;C3〜C6−シクロアルキル;C1〜C4−アルコキシ;C1〜C4−ハロアルコキシ;C1〜C4−ハロアルキルチオ;SF5;N,N−ジ−C1〜C4−アルキルアミノ−C1〜C4−アルキルアミノカルボニル;N−C1〜C4−アルキルスルホニルアミノ;シアノ;ニトロ;ヒドロキシ;B(OH)2;モルホリノ;あるいはそれぞれ、非置換であるかまたはハロゲン、C1〜C4アルキル、C1〜C4ハロアルキル、C3〜C6シクロアルキルもしくはC1〜C4アルコキシによって置換されている、フェニル、ベンゾイル、ピリジルオキシ、ピリミジニルオキシまたはベンゾチアゾリルである、請求項1〜5のいずれか一項に記載の式(I)の化合物。
- 各R1が、独立して、ハロゲン;C1〜C2−アルキル;C1〜C3−ハロアルキル;C1〜C2−アルコキシ;C1〜C3−ハロアルコキシ;C1〜C2−ハロアルキルチオ;SF5;ニトロ;またはヒドロキシである、請求項1〜5のいずれか一項に記載の式(I)の化合物。
- 各R 1 が、独立して、ハロゲンまたはCF 3 である、請求項7に記載の式(I)の化合物。
- rが1、2または3の整数である、請求項1〜8のいずれか一項に記載の式(I)の化合物。
- R0がHであり、mが0または1であり、XがOである、請求項1〜9のいずれか一項に記載の式(I)の化合物。
- 式(Ia’)の請求項1に記載の化合物:
(式中、Rおよびmは、それぞれ請求項1で定義した通りである)。 - 式(Ib)の請求項1に記載の化合物:
(式中、R、R1、mおよびrは、それぞれ請求項1で定義した通りである)。 - mが1または2の整数であり、rが2または3の整数であり、各Rが独立してハロゲンまたはCF3であり、各R1が独立してハロゲンまたはCF3である、請求項12に記載の式(Ib)の化合物。
- 寄生虫の防除のための組成物であって、活性成分としての少なくとも1つの請求項1〜10のいずれか一項に記載の式(I)の化合物、請求項11に記載の式(Ia’)の化合物、または請求項12もしくは13に記載の式(Ib)の化合物、ならびに担体および/または分散剤を含有する、組成物。
- 温血動物の体内または体表上の内部寄生虫の防除における使用のための、請求項1〜10のいずれか一項に記載の式(I)の化合物、請求項11に記載の式(Ia’)の化合物、または請求項12もしくは13に記載の式(Ib)の化合物。
- 温血動物の体内または体表上の内部寄生虫に対する獣医学的組成物または医薬組成物の調製における、請求項1〜10のいずれか一項に記載の式(I)の化合物、請求項11に記載の式(Ia’)の化合物、または請求項12もしくは13に記載の式(Ib)の化合物、の使用。
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